Retrospective Study
Copyright ©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Diabetes. Jan 15, 2024; 15(1): 53-71
Published online Jan 15, 2024. doi: 10.4239/wjd.v15.i1.53
Heterogeneously elevated branched-chain/aromatic amino acids among new-onset type-2 diabetes mellitus patients are potentially skewed diabetes predictors
Min Wang, Yang Ou, Xiang-Lian Yuan, Xiu-Fang Zhu, Ben Niu, Zhuang Kang, Bing Zhang, Anwar Ahmed, Guo-Qiang Xing, Heng Su
Min Wang, Xiu-Fang Zhu, School of Chemical Science and Technology, Yunnan University, Kunming 650091, Yunnan Province, China
Yang Ou, Xiang-Lian Yuan, Ben Niu, Zhuang Kang, Heng Su, Department of Endocrinology, The First People’s Hospital of Yunnan Province, Kunming 650032, Yunnan Province, China
Bing Zhang, Clinical Laboratory, Nanchong Central Hospital & The Second Clinical Medical College of North Sichuan Medical University, Nanchong 637000, Sichuan Province, China
Anwar Ahmed, Department of Preventive Medicine and Biostatistics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, United States
Guo-Qiang Xing, The Affiliated Hospital and Second Clinical Medical College, North Sichuan Medical University, Nanchong 637000, Sichuan Province, China
Guo-Qiang Xing, Department of Research and Development, Lotus LLC, Gaithersburg, MD 20878, United States
Co-first authors: Min Wang and Yang Ou.
Co-corresponding authors: Guo-Qiang Xing and Heng Su.
Author contributions: Wang M, Xing GQ and Su H conceptualized and designed the research; Ou Y, Niu B and Kang Z screened patients and acquired clinical data; Wang M, Yuan XL, Zhang B and Zhu XF collected blood specimen and performed laboratory analysis; Wang M, Ahmed A, Yuan XL and Xing GQ performed Data analysis; Wang M, Su H and Xing GQ wrote the paper. All the authors have read and approved the final manuscript. Wang M proposed, designed and conducted serum amino acids analysis, performed data analysis and prepared the first draft of the manuscript. Ou Y was responsible for patient screening, enrollment, collection of clinical data and blood specimens. Both authors have made crucial and indispensable contributions towards the completion of the project and thus qualified as the co-first authors of the paper. Both Su H and Xing GQ have played important and indispensable roles in the experimental design, data interpretation and manuscript preparation as the co-corresponding authors. Su H applied for and obtained the funds for this research project. Su H conceptualized, designed, and supervised the whole process of the project. He searched the literature, revised and submitted the early version of the manuscript with the focus on the association between visceral adipose tissue (VAT) and BCAA/AAA. Xing GQ was instrumental and responsible for data re-analysis and re-interpretation, figure plotting, comprehensive literature search, preparation and submission of the current version of the manuscript with a new focus on BCAAs/AAAs as the predictors of diabetes and on potential underlying mechanisms. This collaboration between Su H and Xing GQ is crucial for the publication of this manuscript and other manuscripts still in preparation.
Supported by the Open Project Grant for Clinical Medical Center of Yunnan Province, No. 2019LCZXKF-NM03; Medical Leader Training Grant, No. L-201624; and Yunnan Province Ten Thousand Talents: “Medical Expert” grant, No. YNWR-MY-2019-020.
Institutional review board statement: The study was reviewed and approved by the Medical Ethics Review Committee of the First People's Hospital of Yunnan Province [Approval No. 2016(001)].
Informed consent statement: All study participants, or their legal guardian, provided informed written consent prior to study enrollment.
Conflict-of-interest statement: All authors declare no potential conflicts of interest.
Data sharing statement: Data are available from the corresponding authors upon reasonable request.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work noncommercially, and license their derivative works on different terms, provided the original work is properly cited and the use is noncommercial. See:
Corresponding author: Heng Su, MD, PhD, Professor, Department of Endocrinology, the First People’s Hospital of Yunnan Province, No. 157 Jinbi Road, Kunming 650032, Yunnan Province, China.
Received: September 13, 2023
Peer-review started: September 13, 2023
First decision: October 24, 2023
Revised: November 3, 2023
Accepted: December 13, 2023
Article in press: December 13, 2023
Published online: January 15, 2024

The lack of specific predictors for type-2 diabetes mellitus (T2DM) severely impacts early intervention/prevention efforts. Elevated branched-chain amino acids (BCAAs: Isoleucine, leucine, valine) and aromatic amino acids (AAAs: Tyrosine, tryptophan, phenylalanine)) show high sensitivity and specificity in predicting diabetes in animals and predict T2DM 10-19 years before T2DM onset in clinical studies. However, improvement is needed to support its clinical utility.


To evaluate the effects of body mass index (BMI) and sex on BCAAs/AAAs in new-onset T2DM individuals with varying body weight.


Ninety-seven new-onset T2DM patients (< 12 mo) differing in BMI [normal weight (NW), n = 33, BMI = 22.23 ± 1.60; overweight, n = 42, BMI = 25.9 ± 1.07; obesity (OB), n = 22, BMI = 31.23 ± 2.31] from the First People’s Hospital of Yunnan Province, Kunming, China, were studied. One-way and 2-way ANOVAs were conducted to determine the effects of BMI and sex on BCAAs/AAAs.


Fasting serum AAAs, BCAAs, glutamate, and alanine were greater and high-density lipoprotein (HDL) was lower (P < 0.05, each) in OB-T2DM patients than in NW-T2DM patients, especially in male OB-T2DM patients. Arginine, histidine, leucine, methionine, and lysine were greater in male patients than in female patients. Moreover, histidine, alanine, glutamate, lysine, valine, methionine, leucine, isoleucine, tyrosine, phenylalanine, and tryptophan were significantly correlated with abdominal adiposity, body weight and BMI, whereas isoleucine, leucine and phenylalanine were negatively correlated with HDL.


Heterogeneously elevated amino acids, especially BCAAs/AAAs, across new-onset T2DM patients in differing BMI categories revealed a potentially skewed prediction of T2DM development. The higher BCAA/AAA levels in obese T2DM patients would support T2DM prediction in obese individuals, whereas the lower levels of BCAAs/AAAs in NW-T2DM individuals may underestimate T2DM risk in NW individuals. This potentially skewed T2DM prediction should be considered when BCAAs/AAAs are to be used as the T2DM predictor.

Keywords: Hyperaminoacidemia, Branched-chain/aromatic amino acids, New-onset type-2 diabetes, Predictor, Obesity, Sex

Core Tip: Elevated branched-chain amino acids (BCAAs) and aromatic amino acids (AAAs) predict diabetes in animals with high sensitivity and specificity (both > 97%) and predict type-2 diabetes mellitus (T2DM) 10-20 years before T2DM onset. However, our results indicate that heterogeneously elevated BCAAs/AAAs among new-onset T2DM patients in differing BMI categories and sex may skew BCAA/AAA prediction of T2DM development among the general population: the greater BCAA/AAA elevation in obese individuals, especially males, would support T2DM prediction in these individuals, whereas the lack of or reduced BCAA/AAA elevation in NW and reproductive-aged females may compromise BCAA/AAA prediction of T2DM in these individuals. Potential nutritional, metabolic and molecular mechanisms are discussed.